FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a
Miyesaier Abudureyimu,
Xuanming Luo,
Lingling Jiang,
Xuejuan Jin,
Cuizhen Pan,
Wei Yu,
Junbo Ge,
Yingmei Zhang,
Jun Ren
Affiliations
Miyesaier Abudureyimu
Cardiovascular Department, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, 200031, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
Xuanming Luo
National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China; Department of General Surgery, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, 200031, China
Lingling Jiang
Cardiovascular Department, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, 200031, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
Xuejuan Jin
National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
Cuizhen Pan
National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
Wei Yu
Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China
Junbo Ge
National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
Yingmei Zhang
National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
Jun Ren
National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China; Corresponding author. National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
Aims: Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF. Method and results: Adult mice were placed on a high fat diet plus l-NAME in drinking water (‘two-hit’ challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in ‘two-hit’ mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a ‘double-damage’ insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated ‘double-damage’-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca2+ uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na+-Ca2+ exchanger with unaltered SR Ca2+ load. FBXL4 ablated ‘two-hit’ or ‘double-damage’-induced changes in SERCA2a, phospholamban and mitochondrial injury. Conclusion: FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.
